DESCRIPTION: This K99/R00 project will support training and career development of the candidate to become a translational neuroscientist using innovative neuroimaging tools to address clinical relevant questions of substances of abuse disorders. The Candidate has solid background in medical physics and neuroscience imaging. She is seeking further training and mentored research experience in three areas related to addiction research: (1) neuropharmacology and neurobiology of addiction, (2) advanced pharmacological PET/MRI imaging methods, and (3) clinical and translational research skills. The candidate will take didactic coursework, attend seminar and conference, and perform hands-on tutorials and experiments to obtain all needed training. The candidate is keen in addiction research because perturbed brain neurochemistry and consequent changes in brain function are pivotal in all stages of substances abuse disorders. With the recent invention of simultaneous PET/MRI, the candidate has the unique ability to develop novel integrative PET/MRI imaging methods and apply in addiction research. The proposed research project running in parallel to training activities will also facilitate her develop into an independent scientist investigating the neurobiological mechanisms involve in substance of abuse disorders. Opioid drugs are the most effective analgesics for pain management. The amount of opioid prescriptions has increased dramatically over the past years resulting in an accompanied rise in opioid-related abuse and addiction. Opioid overdose deaths from prescribed drugs now surpass that of heroin and cocaine combined. The pursuit for effective analgesics with no or reduced addictive liability remains an urgent need. The long-term goal of this research program is to disentangle neurochemical mechanisms that govern opioid addiction liability to enable faster and more informed drug development for pain management. In this K99/R00 proposal, as the first step towards achieving the long-term goal, we aim to characterize opioid-agonist evoked opioid receptor regulation and to elucidate its functional consequences in vivo using novel PET/MRI methods. We will develop innovative PET/MRI neurochemical model and establish a new framework for evaluating opioid agonist drugs. Successful completion of this project will (1) establish a knowledge basis of opioid receptor regulation on opioid-dopamine interactions and its relation to abuse liability; (2) enable a PET/MRI imaging metric for assessing abuse liability f novel medications; and (3) permit the use of PET/MRI tools for testing emerging hypotheses in addiction research.